Cardioprotective Activity of Pharmacological Agents Affecting NO Production and Bioavailability in the Early Postnatal Period after Intrauterine Hypoxia in Rats

Abstract

Intrauterine hypoxia in newborns leads to a multifaceted array of alterations that exert a detrimental impact on the cardiovascular system. The aim of this research was to assess the cardioprotective effects of modulators of the nitric oxide (NO) system, including L-arginine, Thiotriazoline, Angiolin, and Mildronate, during the early postnatal period following intrauterine hypoxia. Methods: The study involved 50 female white rats. Pregnant female rats were given a daily intraperitoneal dose of 50 mg/kg of sodium nitrite starting on the 16th day of pregnancy. A control group of pregnant rats received saline instead. The resulting offspring were divided into the following groups: Group 1—intact rats; Group 2—rat pups subjected to prenatal hypoxia (PH) and daily treated with physiological saline; and Groups 3 to 6—rat pups exposed to prenatal hypoxia and treated daily from the 1st to the 30th day after birth. Nitrotyrosine levels, eNOS, iNOS, and NO metabolites were evaluated using ELISA; to measure the expression levels of iNOS mRNA and eNOS mRNA, a PCR test was utilized. Results: Angiolin enhances the expression of eNOS mRNA and boosts eNOS activity in the myocardium of rats with ischemic conditions. Arginine and particularly Thiotriazoline exhibited a consistent impact in restoring normal parameters of the cardiac nitroxidergic system following PH. Mildronate notably raised iNOS mRNA levels and notably reduced nitrotyrosine levels, providing further support for its antioxidative characteristics.

Modulating Nitric Oxide: Implications for Cytotoxicity and Cytoprotection

“…For instance, recent findings have demonstrated that inhibition of mitochondrial nitric oxide synthase (mtNOS) results in the accumulation of intramitochondrial Ca 2+ , indicating that • NO produced by mtNOS impedes Ca 2+ accumulation. Given that the elevation in matrix Ca 2+ concentration is responsible for altering mitochondrial membrane permeability, it is deduced (contrary to the earlier assertion) that mitochondrial • NO decelerates the opening of the mitochondrial permeability transition pore and the subsequent release of cytochrome C [117][118][119][120][121][122][123]. While there are indications that the synthesis of • NO may be regulated through substrates of mtNOS (such as L-Arginine, NADPH) and its cofactors (including FMN, FAD, BH4), akin to other NOS isoforms, this aspect remains largely unexplored.…”

Hacking the Lipidome: New Ferroptosis Strategies in Cancer Therapy

“…Thiothriazoline [ 149 ], thiometrizole (discovered at Zaporizhzia State Medical and Pharmaceutical University in Ukraine), and other thio-1,2,4-triazoles [ 150 , 151 , 152 , 153 , 154 , 155 ] have been identified as highly effective antioxidants and need to be tested as potential agents for relaxing oxidative stress and reprogramming the lipidome towards elevated PUFA levels.…”

Nitric Oxide in the Mechanisms of Cell Death and Cytoprotection

“…For instance, recent findings have demonstrated that inhibition of mitochondrial nitric oxide synthase (mtNOS) results in the accumulation of intramitochondrial Ca2+, indicating that NO produced by mtNOS impedes Ca2+ accumulation. Given that the elevation in matrix Ca2+ concentration is responsible for altering mitochondrial membrane permeability, it is deduced (contrary to the earlier assertion) that mitochondrial NO decelerates the opening of the mitochondrial permeability transition pore and the subsequent release of cytochrome C [117][118][119][120][121][122][123]. While there are indications that the synthesis of NO may be regulated through substrates of mtNOS (such as L-Arginine, NADPH) and its cofactors (including FMN, FAD, BH4), akin to other NOS isoforms, this aspect remains largely unexplored.…”